The present invention relates to novel compounds, and it relates to novel compounds which enhance the physiological activity of the ligands to intranuclear receptors whose typical examples include retinoic acid and compounds having retinoic acid-like actions (retinoids).
Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation, and life support action. It has been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. (Sho)61-22047/1986 and (Sho)61-76440/1986 and the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p.2182. xe2x80x9cRetinoidsxe2x80x9d is a general term for retinoic acid and the aforementioned compounds having retinoic acid-like biological activities.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cell nuclei, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p.889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities (Petkovich, M., et al., Nature, 330, pp.444-450, 1987). It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities, e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid: Am80, also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990). Clinically, these compounds were found as useful for the therapeutic and preventive treatment of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone disease, leukemia and certain types of cancer.
Compounds are known which antagonize against these retinoids and reduce the primary actions of the retinoid (Eyrolles, L., et al., Journal of Medicinal Chemistry, 37(10), pp.1508-1517, 1994). However, a compound has not been known, other than those disclosed in EP 694,301 A1, which enhances the actions of the retinoids such as retinoic acid, while the compound, per se, has no retinoid action or its retinoid actions are negligible. In this publication, it is suggested that a ligand compound specific to RXR receptor has an enhancing activity on Am80, i.e., a ligand specific to RAR-xcex1-receptor.
An object of the present invention is to provide compounds having enhancing activities on the actions of the retinoids such as retinoic acid. More specifically, the object of the present invention is to provide compounds which can remarkably enhance the action of retinoids such as retinoic acid, while the compounds, per se, have no retinoid action or their retinoid actions are very weak.
The inventor of the present invention conducted various studies to achieve the foregoing object, and as a result, found that the compounds represented by the general formulas set out below enhance the action of retinoids such as retinoic acid. The present invention was achieved on the basis of the findings.
The present invention thus provides the compounds or the salts thereof represented by the following formula (I): 
or the following formula (II): 
wherein, R1 represents hydrogen atom or a C1-6 alkyl group; R2 and R3 independently represent a hydrogen atom or a C1-6 alkyl group, or R2 and R3 may combine together with the carbon atoms of the phenyl ring to which R2 and R3 bind to represent a 5- or 6-membered cycloalkyl group which may optionally be substituted with one or more C1-4 alkyl groups; R4 represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, hydroxyl group, nitro group, or a halogen atom; R5 represents a hydrogen atom, a C1-6 alkyl group, or an aryl-substituted C1-6 alkyl group; R6 represents a hydrogen atom or a C1-6 alkyl group; X represents xe2x80x94NR7xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CHR7xe2x80x94 or xe2x80x94Sxe2x80x94 in which R7 represents a hydrogen atom, a C1-6 alkyl group, or an aryl-substituted C1-6 alkyl group; and Y represents a phenylene group or a pyridinediyl group. In addition, according to further embodiments of the present invention, there are provided a medicament comprising the aforementioned compounds; an agent enhancing the actions of the retinoid which comprises the aforementioned compounds; and an agent enhancing the actions of the ligands to the intranuclear receptors which comprises the aforementioned compounds.
In the above general formula (I), R1 represents a hydrogen atom or a linear or branched C1-6 (i.e., having 1 to 6 carbon atoms) alkyl group. Examples of the alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group, and methyl group is preferably used.
R2 and R3 independently represents a hydrogen atom or a linear or branched C1-6 alkyl group. As for the alkyl group, those mentioned above may be used, and ethyl group, isopropyl group, tert-butyl group or the like may preferably be used. Each of R2 and R3 may independently substitute at any position and their substituting positions are not particularly limited. However, it is preferable that R2 and R3 are at para-position and meta-position with reference to X, respectively, R2 and R3 are at meta-position and ortho-position with reference to X. It is particularly preferable that R2 and R3 are at para-position and meta-position with reference to X, respectively.
R2 and R3 may combine to form a 5- or 6-membered cycloalkyl ring together with two carbon atoms on the phenyl ring to which R2 and R3 respectively bind. The cycloalkyl ring may have one or more C1-4 alkyl groups. For example, the ring may have from two to four methyl groups, preferably four methyl groups. For example, it is preferable that R2 and R3 together with the phenyl ring substituted with R2 and R3 may form 5,6,7,8-tetrahydronaphthalene ring or 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring.
R4 represents a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, hydroxyl group, nitro group, or a halogen atom. As the C1-6 alkyl group, these exemplified above may be used. As the C1-6 alkoxy group, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, or tert-butoxy group, preferably methoxy group, may be used. As the halogen atom, any of fluorine atom, chlorine atom, bromine atom, or iodine atom may be used. R4 may substitute at any position on the phenyl ring and its position is not particularly limited.
R5 represents a hydrogen atom, a C1-6 alkyl group, or an aryl-substituted C1-6 alkyl group. The C1-6 alkyl group may be either linear or branched and those mentioned above may preferably be used. Examples of the aryl moiety of the aryl-substituted C1-6 alkyl group include, for example, phenyl, naphthyl, or pyridyl group, and the C1-6 alkyl moiety may be either linear or branched. For example, a phenyl-substituted C1-6 alkyl group such as benzyl group or phenethyl group, a naphthyl-substituted C1-6 alkyl group such as naphthylmethyl group, or a pyridyl-substituted C1-6 alkyl group such as pyridylmethyl group can be used.
The aryl group constituting these aryl-substituted C1-6 alkyl group may have one or more substituents. For example, a halogen atom such as fluorine atom or chlorine atom; a C1-6 alkyl group such as methyl group or ethyl group; a linear or branched C1-6 alkoxy group such as methoxy group or ethoxy group; nitro group; a linear or branched halogenated C1-6 alkyl group such as trifluoromethyl group; hydroxyl group; carboxyl group; or a C1-6 alkoxycarbonyl group such as methoxycarbonyl group or ethoxycarbonyl group may be used as the substituent. R6 represents a hydrogen atom or a C1-6 alkyl group. The C1-6 alkyl group may be either linear or branched and those explained above may preferably used. The compound wherein both of R5 and R6 are hydrogen atoms, and the compound wherein R5 is a C1-6 alkyl group or an aryl-substituted C1-6 alkyl group and R6 is a hydrogen atom are particularly preferred compounds.
X represents a nitrogen atom substituted with R7 (xe2x80x94NR7xe2x80x94), an oxygen atom (xe2x80x94Oxe2x80x94), a methylene group substituted with R7 (xe2x80x94CHR7xe2x80x94), or a sulfur atom (xe2x80x94Sxe2x80x94). R7 represents a hydrogen atom, a C1-6 alkyl group, or an aryl-substituted C1-6 alkyl group. The C1-6 alkyl group may be either linear or branched and those exemplified above, e.g., methyl group, may be used. As the aryl-substituted C1-6 alkyl group, those exemplified above, preferably benzyl group, may be used. The nitrogen atom and the sulfur atom may be in the form of N-oxide and sulfoxide, respectively. Among them, X may preferably be a nitrogen atom substituted with R7 (NR7), and X most preferably represents a nitrogen atom substituted with methyl group, ethyl group, n-propyl group, isopropyl group, or benzyl group.
Y represents a phenylene group or a pyridinediyl group. For example, any one of phenylene groups or pyridinediyl groups such as p-phenylene group, m-phenylene group, o-phenylene group, pyridine-2,4-diyl group, pyridine-2,5-diyl group, or pyridine-3,5-diyl group may be used. Preferably, p-phenylene group, m-phenylene group, or pyridine-2,5-diyl group may be used. Where pyridine-2,5-diyl group is used, the group represented by xe2x80x94COOR1 may substitute either at 2-position or 5- position of the pyridine ring.
Acid addition salts and base addition salts fall within the scope of the compounds of the present invention. Examples of the acid addition salts include mineral acid salts such as hydrochloride or hydrobromide and organic acid salts such as p-toluenesulfonate, methanesulfonate, oxalate, or tartrate. The base addition salts may be formed where R1 represents a hydrogen atom. Metal salts such as, for example, sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salts, or organic amine salts such as, for example, triethylamine salt or ethanolamine salt, for example, may be used.
As for the compounds of the present invention represented by formula (II), where R5 and R6 are different substituents to each other, the carbon atom substituted thereby is recognized as an asymmetric carbon. On the assumption that, in the formula (II), the 7-membered ring containing X forms a plane, either R5 or R6 may be above the plane. In addition, the compounds of the formula (I) and the formula (II) of the present invention may have one or more additional asymmetric carbons depending on the sorts of X and other substituents. Any optical isomers based on one or more of such asymmetric carbons, any mixture of optical isomers, racemates, any diastereomers based on two or more asymmetric carbons, any mixtures of the diastereomers and the like fall within the scope of the present invention. It should also be understood that any hydrates or solvates of the compounds in the free forms or those of the compounds in the forms of salts also fall within the scope of the present invention.
Among the compounds of the present invention represented by the above formula (I), preferable examples include:
4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]-diazepine-11-yl]benzoic acid (HX600);
4-[5H-2,3-diisopropyl-5-methyldibenzo[b,e][1,4]diazepine-11-yl]benzoic acid (HX610);
4-[5H-2-tert-butyl-5-methyldibenzo[b,e][1,4]diazepine-11-yl]benzoic acid (HX511);
4-[5H-3,4-(1,4-butano)-5-methyldibenzo[b,e][1,4]diazepine-11-yl]benzoic acid (HX545);,
4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e]-[1, 4]-diazepine-11-yl]benzoic acid (HX531);
4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]oxazepine-11-yl]benzoic acid (HX620);
4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,f][1,4]thiazepine-11-yl]benzoic acid (HX630);
5-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]-diazepine-11-yl]-2-pyridinecarboxylic acid;
6-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]-diazepine-11-yl]-3-pyridinecarboxylic acid; and
4-[2,3-(2,5-dimethyl-2,5-hexano)dibenzo[b,e]azepine-11-yl]benzoic acid (HX640),
and lower alkyl esters of the above respective compounds, preferably methyl esters (for example, as for HX600, methyl 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]diazepine-11-yl]benzoate).
Among the compounds of the present invention represented by the formula (II), examples of preferred compounds include, for example, those listed in the table set out below. In these compounds, R1 is a hydrogen atom or methyl group, Y is p-phenylene group, and X is xe2x80x94NR7xe2x80x94. The symbol xe2x80x9cBzlxe2x80x9d represents benzyl group, and descriptions such as 7-Me, 8-Et, 8-i-Pro, and 9-t-Bu represent that the compound of formula (II) is substituted with methyl group at the 7-position, ethyl group at the 8-position, isopropyl group at the 8-position, and tert-butyl group at the 9-position, respectively. The descriptions such as 7-(CH2)4-8 and 7-C(CH3)2CH2CH2C(CH3)2-8 represent that the 7-position and the 8-position of the compounds of the formula (II) are bound with xe2x80x94(CH2)4xe2x80x94 and xe2x80x94C(CH3)2 CH2 CH2 C(CH3)2xe2x80x94, respectively.
Among these, examples of particularly preferred compounds include:
4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano )-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX800);
4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-1-methyl-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX801);
4-[3(S)-methyl-1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX810);
4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-1-isopropyl-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX803);
4-[1-benzyl-1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX805); and
4-[3(S)-benzyl-1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoic acid (HX850),
and lower alkyl esters of the above respective compounds, preferably, methyl esters (for example, as for HX800, methyl 4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepine-5-yl]benzoate). 
With reference to HX600, HX610, HX511, HX531 and HX545, as being preferred compounds that fall within the formula (I) of the present invention, exemplary preparing methods are shown in the schemes set out below. In addition, as for HX800, HX801 and HX850 being preferred compounds falling within the formula (II) of the present invention, exemplary preparing methods are shown in the same manners in the following schemes. However, the compounds of the present invention and the preparation methods thereof are not limited to those shown in the schemes. The preparation methods of the compounds of the present invention according to the schemes below are further detailed in the examples given in the specification. Therefore, it can be readily understood that any compounds falling within the scope of the present invention can be prepared by appropriately modifying or altering the starting materials, reagents, reaction conditions and the like disclosed in these exemplified methods. 
The compounds of the present invention, per se, have substantially no retinoid-like activity, or they have slight or moderate retinoid-like activities. However, where the compounds of the present invention is subjected to coexistence with a retinoid such as retinoic acid, the physiological activities of the retinoid (typical examples include cell differentiation activity, cell proliferation enhancing activity, life supporting activity and the like) are markedly enhanced.
Although it is not intended to be bound by any specific theory, where a compound of the present invention has retinoid actions, the actions are synergistic. Therefore, where retinoic acid or the aforementioned compounds having the retinoic acid-like biological activities (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid: Am80) are administered as medicaments for the preventive or therapeutic treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, psoriasis, allergic diseases, immunological diseases such as rheumatism, bone diseases, leukemia, or cancers, the compounds of the present invention can be used as agents that enhance the activities of the retinoids.
Where the retinoids are not administered for the preventive and therapeutic treatments of the aforementioned diseases, the compounds of the present invention can enhance the activities of retinoic acid inherently existing in living bodies, and thus, the compounds of the present invention, per se, may be administered for the purpose of the preventive and therapeutic treatments of the aforementioned diseases. Furthermore, the compounds of the present invention may be used, in addition to the enhancement of the action of the retinoids, to enhance the activities of physiologically active substances such as, for example, steroid compounds, vitamin D compounds such as vitamin D3, thyroxine and the like that bind to receptors belonging to the intranuclear receptor super family and existing in cell nuclei (Evans, R. M., Science, 240, p.889, 1988).
The medicament comprising the compounds of the present invention may be administered, per se. However, it is preferable that pharmaceutical compositions for oral administrations or parenteral administrations may be administered which can be prepared by methods well known to those skilled in the art. The compounds may be added to medicaments comprising as an active ingredient a retinoid such as retinoic acid, and used as pharmaceutical compositions in the form of so-called combined formulations. Examples of the pharmaceutical compositions suitable for oral administrations include, for example, tablets, capsules, powders, subtilize granules, granules, liquids, syrups and the like. Examples of the pharmaceutical compositions suitable for parenteral administrations include, for example, injections, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches and the like.
The aforementioned pharmaceutical compositions may be prepared by the addition of pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrators and disintegrating aids, binders, lubricants, coating agents, colorants, diluents, base materials, dissolving agents and dissolving aids, isotonic agents, pH modifiers, stabilizers, propellants, tackifiers and the like.
The doses of the medicament of the present invention are not particularly limited, and suitable doses can appropriately be chosen for any administration methods whose examples include, for example, where the actions of a retinoid is enhanced by using the medicament of the present invention in combination with the medicament comprising said retinoid such as retinoic acid as an active ingredient, or where the medicament of the present invention is administered to enhance the actions of retinoic acid inherently exist in a living body. For example, for oral administrations, the medicament may be used in a dose of 0.01-1,000 mg per day for adults. Where the medicament of the present invention is used in combination with a medicament comprising a retinoid as an active ingredient, the medicament of the present invention can be administered in any periods of time, i.e., during the period of the retinoid administration or before or after said period.